A variety of methods for the treatment of tumors have hitherto been attempted, including surgical operation, radiotherapy, physiotherapy such as thermatology and chemotherapy, alone or in combinations. In particular, surgical operation and radiotherapy are highly effective in removing primary tumors. Even if, however, an earlier detection of a primary tumor and the removal thereof by surgical operation are successful, the possible metastasis of the tumor may often bring about death of the patient. Furthermore, tumors in organs or regions where surgical operation is impossible can only be treated by means of physiotherapy or chemotherapy. In such case, possible metastatic tumors in other regions of the body may often lead to death of the patient, even if growth of the primary tumor is successfully inhibited. Thus, one of the most difficult problems in tumor treatment is to inhibit metastasis.
The metastatic process of tumor consists of several steps including release of cells from primary tumors, transfer thereof via vessels, adhesion to the other organs, and infiltration and proliferation of the tumor cells therein. The defense mechanism of organism participates in said steps. Recently, complex mechanism of tumor metastasis has partly been elucidated but the total mechanism has not been clarified.
Many studies have been made on development of medicaments for inhibiting tumor metastasis, with little successful results.
The mechanism of tumor metastasis is complicated and has not clarified completely. However, the relation between metastatic potential of tumor cells and structure of N-glycosidically linked saccharide chain on cell surface have been investigated relatively well and some important findings have been obtained. It was known that most of tumor cells have increased branching in N-glycosidically linked saccharide chain on cell surface in comparison with normal cells, and that such increase is due to the increase in the special GlcNAc.beta.1-6Man structure (wherein GlcNAc stands for N-acetyl glucosamine and Man stands for mannose) in the saccharide chain. Recently, James W. Dennis et al. (Science Vol. 236, 582-585, May 1987) has reported that the presence of GlcNAc.beta.1-6Man structure is directly associated with the metastatic potential of tumor cells, and the tumor cells having more such structure exhibit higher metastatic potential.
The increase and decrease in GlcNAc.beta.1-6Man structure on the tumor cell surface can be determined using L-PHA, a kind of lectin. L-PHA binds specifically to saccharide chains containing GlcNAc.beta.1-6Man structure and inhibits the proliferation of the cells depending upon the amount of said structure present (Science Vol. 236, 582-585, May 1987). Therefore, the increase and decrease in GlcNAc.beta.1-6Man structure can be determined by measuring the L-PHA sensitivity (susceptibility to inhibition of proliferation by L-PHA) of the specific tumor cells.
We have investigated the effect of many compounds on L-PHA sensitivity of tumor cells utilizing the above mentioned properties of tumor cells, and found that polyprenols and polyprenyl phosphates permit the reduction in L-PHA sensitivity of tumor cells, i.e., the reduction in GlcNAc.beta.1-6Man structure. From these facts, we have found that polyprenols and polyprenyl phosphates can effectively inhibit tumor metastasis.
Some of polyprenols and polyprenyl phosphates are disclosed in Jpn. J. Cancer Res. (Gann), 76, 760-770, August 1985 and Japanese Patent LOP Publication No. 39521/1987. However, there is no reference to their pharmaceutical uses as a medicament for the inhibition of tumor metastasis.
The present invention results from efforts to develop a new use of polyprenols and polyprenyl phosphates for the inhibition of tumor metastasis.